Interaction between γδTCR signaling and the E protein-Id axis in γδ T cell development

gamma delta T cells acquire their functional properties in the thymus, enabling them to exert rapid innate-like responses. To understand how distinct gamma delta T cell subsets are generated, we have developed a Two-Stage model for gamma delta T cell development. This model is predicated on the finding that gamma delta TCR signal strength impacts E protein activity through graded upregulation of Id3. Our model proposes that cells enter Stage 1 in response to a gamma delta TCR signaling event in the cortex that activates a gamma delta T cell-specific gene network. Part of this program includes the upregulation of chemokine receptors that guide them to the medulla. In the medulla, Stage 1 cells receive distinct combinations of gamma delta TCR, cytokine, and/co-stimulatory signals that induce their transit into Stage 2, either toward the gamma delta T1 or the gamma delta T17 lineage. The intersection between gamma delta TCR and cytokine signals can tune Id3 expression, leading to different outcomes even in the presence of strong gamma delta TCR signals. The thymic signaling niches required for gamma delta T17 development are segregated in time and space, providing transient windows of opportunity during ontogeny. Understanding the regulatory context in which E proteins operate at different stages will be key in defining how their activity levels impose functional outcomes.